The principal pharmacological effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase activities..sup.1-6 Prostaglandins are derived from arachidonic acid and the their biosynthesis occurs in three stages: (1) hydrolysis of arachidonate from phospholipid precursors, most likely catalyzed by phospholipase A.sub.2 ; (2) oxygenation of arachidonate to prostaglandin endoperoxide H.sub.2 (PGH.sub.2), catalyzed by two closely related isozymes, prostaglandin endoperoxide H synthase-1 and -2 (i.e. cyclooxygenase-1 and -2 or COX-1 and COX-2); (3) conversion of PGH.sub.2 to a biologically active end-product (e.g. PGE.sub.2, PGF.sub.2a, PGI.sub.2), catalyzed by individual enzymes. Compounds which inhibit prostaglandin synthesis are anti-inflammatory, anti-pyretic and analgesic. Common side effects of NSAIDs frequently limit their therapeutic use. Typical side effects associated with NSAID therapy are gastrointestinal (GI) and renal. These side effects were believed to be inseparable from the pharmacological effects since prostaglandins have cytoprotective effects in the gastrointestinal tract and also regulate renal blood flow.
The discovery that there are two isozymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), that catalyze the second step in prostaglandin synthesis has provided the possibility to separate the 1 pharmacological effects from the side effects of NSAIDs. Research results suggest that the COX-1 and COX-2 belong to separate prostaglandin-forming systems. COX-1 is expressed constitutively in most cells and tissues..sup.7-9 The COX-1-dependent pathway can respond instantaneously and produces prostaglandins that regulate acute events such as vascular homeostasis. The synthesis of prostagladins by COX-1 also helps maintain normal stomach and renal function. COX-2 is only expressed following mitogenic or inflammatory stimuli. Since it is not expressed in most resting tissues and must be induced, prostaglandins produced by COX-2 are probably involved only secondarily in prolonged physiological reactions. This discovery has now given a reason to believe that the gastrointestinal and renal side effects of the nonsteroidal antiinflammatory drugs can be avoided.